Paola Rovagnati

Influence of S-adenosyl-L-methionine on irreversible binding of ethynylestradiol to rat liver microsomes, and its implication in bile secretion.

Abstract A three-day administration of ethynylestradiol (EE) (5 mg/kg per day) is shown to decrease the bile flow in the rat by reducing both the bile salt dependent and independent fractions of the bile. Protection against this effect is observed in rats given S -adenosyl- l -methionine (SAMe) in addition to EE. The protection is accompanied by a significant decrease of the binding of EE to liver microsomal proteins suggesting that SAMe administration may favour the estrogen elimination as a methylated derivative.

Effects of Phlebotomy on Urinary Porphyrin Pattern and Liver Histology in Patients with Porphyria Cutanea Tarda

Urinary porphyrin profiles and liver histology have been investigated in a group of adult alcoholics with porphyria cutanea tarda (PCT) before and after one year phlebotomy. Both parameters were evaluated during the same period in a group of patients who did not undergo specific therapy for PCT. All patients were advised to abstain from alcohol. At the end of the one year observation period there was a significant fall of urinary total porphyrins and in the uro/coproporphyrin ratio in treated patients compared to basal values whereas no changes were found in controls. Liver biopsy findings revealed a significant reduction of hepatic fatty degeneration and siderosis with no changes in inflammatory infiltrates and fibrosis in treated patients, so the progression of liver disease was similar to controls. These results show that clinical and biochemical remission of PCT can occur independently of the evolution of the concomitant liver disease.

Decreased Blood Levels of Ethanol and Acetaldehyde by S-Adenosyl-L-Methionine in Humans

In view of the protective effects of SAM on alcohol-induced fatty liver degeneration, an investigation has been carried out to see if this compound accelerates the clearance of ethanol and acetaldehyde in humans. Both parameters were significantly lower after SAM, indicating the capability of exogenous SAM to favour the inactivation of ethanol without increasing blood levels of acetaldehyde.

Bile secretion and liver microsomal mixed function oxidase system in mice with griseofulvin-induced hepatic protoporphyria

Administration of 2.5% griseofulvin in the diet to male CD1 mice produced protoporphyria and cholestasis. Protoporphyria became evident as early as after 10 days of treatment, whereas cholestasis, expressed in terms of total bile flow reduction, developed only after 45 days of griseofulvin. Bile flow impairment was due both to the length of treatment and to the severity of liver protoporphyria. Griseofulvin administration was also associated with a significant modification of the relative amounts of hepatic microsomal cytochromes P-450 and b5, a loss in concentration/mg of protein of cytochrome P-450 and a concomitant increase of b5. Despite these changes, the activity of aniline hydroxylase expressed per mg of microsomal protein, assessed in vitro, was not modified.

3-hydroxy-3-methylglutaric acid (HMGA) reduces dietary cholesterol induction of saturated bile in hamster

3-Hydroxy-3-methylglutaric acid (HMGA) is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoAR) and strongly reduces cholesterol biosynthesis both in vitro and in vivo. Since the effects of this compound on biliary lipid composition are hitherto unknown, we have investigated whether it prevents dietary cholesterol induction of saturated bile in the hamster. Female Golden Syrian hamsters have been divided into four groups and treated for 10 weeks as follows: I) Standard diet, containing 0.8 mg cholesterol/g food; II) Standard diet plus HMGA (100 mg/kg b.w./day per os); III) Lithogenic diet containing 2.4 mg cholesterol/g food; IV) Lithogenic diet plus HMGA as above. The results indicate that HMGA is effective in reducing both bile cholesterol supersaturation and hypercholesterolemia. Inhibition of hepatic cholesterogenesis at the level of mevalonate synthesis by HMGCoAR and reduction of intestinal cholesterol absorption may be responsible for these effects.

Effect of Ethanol on Biliary Unconjugated Bilirubin and Its Implication in Pigment Gallstone Pathogenesis in Humans

Though some epidemiological investigations support the association between pigment gallstone formation and chronic alcoholism with cirrhosis, little attention has been paid to the influence of alcohol itself on biliary bilirubin secretion, so that the pathogenesis of pigment cholelithiasis in alcoholics is hitherto unknown. On different days we intravenously administered ethanol (0.7 g/kg body weight), diluted with 500 ml of saline, or saline alone to 6 non-obese patients with an indwelling T tube and reestablished enterohepatic bile circulation. At the time of the investigation bile cultures were negative for aerobic and anaerobic bacteria. Ethanol significantly increased biliary unconjugated bilirubin in respect to control values. The phenomenon reached a maximum 2 h after alcohol infusion when the value of unconjugated bilirubin averaged 2.37 +/- 0.30% of total bilirubin in contrast to 0.65 +/- 0.14% in control conditions (p less than 0.01), and subsided 6 h after the end of ethanol infusion. Since increased amounts of biliary unconjugated bilirubin predispose to pigment stone formation, it can be speculated that alcohol contributes to pigment cholelithiasis pathogenesis by enhancing the biliary concentrations of this form of pigment.

Acute ethanol administration increases biliary concentrations of total and unconjugated bilirubin in rabbits

Epidemiological investigations have revealed that alcoholic cirrhosis is associated with a high frequency of pigment gallstones, but only scantly information is available on the effects of ethanol on biliary secretion of bilirubin. We have injected intravenously 1.0 and 1.5 g/kg body wt of ethanol into six cholecystectomized rabbits with a common bile duct fistula. Experiments were performed ten days after surgery and a stream-splitting apparatus was interposed in the circuit in order to withdraw continuously biliary samples without interruption of enterohepatic bile circulation. Analysis of hourly data showed that both ethanol doses significantly increase the biliary concentration of total bilirubin, without affecting bile flow and lipid composition. Alcohol also promoted the efflux of unconjugated bilirubin into bile. The maximum effect occurred within the first 5 hr following alcohol administration. Thereafter the bile returned to normal. Since excessive concentrations of biliary unconjugated bilirubin favor pigment gallstone development, it can be speculated that alcohol acts as a risk factor for pigment lithiasis by enhancing the biliary levels of this form of pigment.

Effects of compactin (ML-236 B) on biliary lipid composition and cholesterol catabolism in the hamster

Summary The effects of compactin (ML-236 B) administration on bile saturation and on the activity of hepatic HMG-CoA reductase, acylCoA cholesterol acyl transferase and cholesterol 7α-hydroxylase were studied in hamsters fed either a standard or a lithogenic diet. In control animals, treatment with this compound resulted in a stimulation of HMG-CoA reductase associated with supersaturation of the bile. Hypercholesterolemic hamsters in which compactin reduced plasma cholesterol levels responded to the treatment with a decrease of both HMG-CoA reductase and cholesterol 7α-hydroxylase activities. Supersaturation of the bile induced by the lithogenic diet was not modified by compactin.

Effects of iron overload on bile secretion and hepatic porphyrin metabolism in ethinyl extradiol-treated rats

We investigated the effects of ethinyl estradiol (5 mg/kg body wt daily for 5 days, orally) and/or iron sorbitol (50 mg/kg body wt daily for 5 days, i.m.) on bile flow, bile salt independent fraction (BSIF), hepatic delta-aminolevulinate synthase (ALA-S) and uroporphyrinogen decarboxylase (URO-D) in female rats. Ethinyl estradiol administration was associated with a significant decrease of bile flow and BSIF and an increase in URO-D activity in comparison to control values. Iron alone did not modify biliary parameters, but significantly increased the activity of ALA-S. Combined treatment with ethinyl estradiol plus iron partially corrected the reduction of BSIF and restored the activity of ALA-S and URO-D to control levels. Thus iron appears to exert a partially protective effect against ethinyl estradiol-induced cholestasis. No porphyrinogenic effect was observed.

Spontaneous reversal of ethinyl estradiol-induced cholestasis in the rat

The spontaneous reversal of ethinyl estradiol-induced cholestasis has been documented 7 days after the last estrogen administration in the rat. This finding supports the hypothesis that estrogens produce only a transient functional failure of the hepatocytic structures responsible for bile secretion.